Histone and DNA methyltransferases in optic nerve regeneration

项目总结 成年哺乳动物中枢神经系统中的成熟神经元，包括视网膜神经节细胞(RGC)，其 轴突形成视神经，不能再生。这是恢复视力的一个重大挑战 患有视神经损伤或疾病的患者，如青光眼，这是一种影响8000万人的视神经疾病 全球各地的人。我实验室的长期研究表明，视神经延长是一种程序化的 发育过程中的事件，其关闭是导致视神经再生失败的关键原因。 潜在地，表观遗传修饰可能会重新编程神经元，通过重新激活祖细胞来恢复这种能力 在神经成熟过程中被沉默的基因。甲基化，一种关键的表观遗传机制 组蛋白甲基转移酶(HMTs)和DNA甲基转移酶(DNMTs)在视网膜形成中起重要作用。 甲基化水平和甲基转移酶活性的增加与衰老和视网膜高度相关 疾病的发展。然而，表观遗传因子HMTs和DNMTs在RGC中的作用 变性，或称青光眼，目前尚不清楚。通过检查与以下方面相关的特定表观遗传学变化 在小鼠视网膜神经节细胞中，我们最近检测到一个主要的hmt，zust同源基因增强子1(Ezh1)的动态表达。 和DNMTs的关键成员，与视网膜神经发生和视神经再生呈负相关 RGCs的容量。重要的是，我们的初步研究发现，小分子对Ezh1或Dnmts的PAN抑制 化合物促进原代视网膜节细胞和携带选择性DNMT缺陷小鼠的轴突生长 在RGCs中，在体外和体内损伤的视神经中，RGCs促进了健壮的轴突再生长。我们假设 重置Ezh1或Dnmts诱导的发育表观遗传程序可促进再生能力 对视神经的影响。这一假说将在两个特定的目标中进行检验：(1)利用分子事件 Ezh1和Dnmts在体外调节RGC轴突生长；(2)检测Ezh1或Dnmts在视神经中的作用 体内神经生长。这项研究将促进我们对神经发生的表观遗传调控的了解， 有可能发现针对神经退行性疾病的新治疗策略。

Project summary Mature neurons in the central nervous system of adult mammals, including retinal ganglion cells (RGCs) whose axons form the optic nerve, are incapable of regenerating. This presents a major challenge to restoring vision in patients with optic nerve injury or diseases, such as glaucoma, an optic nerve disease that affects 80 million people globally. Long-standing works from my laboratory demonstrate that optic nerve elongation is a programed event during development whose shut-down contributes critically to the failure of optic nerve regeneration. Potentially, epigenetic modification may reprogram neurons to regain this capacity by reactivating progenitor cell genes that have been silenced during neural maturation. Methylation, a key epigenetic mechanism carried out by histone methyltransferases (HMTs) and DNA methyltransferases (DNMTs), is essential in retinogenesis. Increased levels of methylation and methyltransferases activity is highly correlated with aging and retinal diseases progression. However, the functional role of epigenetic factors HMTs and DNMTs in RGC degeneration, or glaucoma in general, is unclear. By examining specific epigenetic changes associated with RGCs in mouse, we recently detected dynamic expression of a major HMT, enhancer of zeste homolog 1 (Ezh1) and a key member of DNMTs, that inversely correlate with retinal neuritogenesis and the optic nerve regenerative capacity of RGCs. Importantly, our pilot study found that pan inhibition of Ezh1 or DNMTs by small-molecule compounds increased neurite outgrowth in primary RGCs in vitro, and mice carrying selective DNMT deficiency in RGCs promoted robust axon re-growth in vitro and in injured optic nerve in vivo. We hypothesized that resetting the developmental epigenetic program induced by Ezh1 or DNMTs promotes the regenerative capacity of the optic nerve. The hypothesis will be tested in two specific aims: (1) Exploit the molecular events by which Ezh1 and DNMTs regulate RGC neurite growth in vitro, and (2) Examine the role of Ezh1 or DNMTs in optic nerve growth in vivo. This study will advance our knowledge about the epigenetic modulation of neuritogenesis, with the potential of discovering novel therapeutic strategies against neurodegenerative diseases.